Project Summary Lung and bronchial cancers remain the leading cause of cancer related deaths in both men and women worldwide. CT-guided percutaneous RF and MW thermal ablation has been shown to provide local control and survival benefit for treatment of small lung tumors, but with limitations imposed upon treatable or accessible regions, lack of spatial and dynamic control of ablative therapy to effectively destroy larger tumors, and frequent complications such as pneumothorax. There remains a substantial and unmet clinical need for a minimally-invasive technology for ablation of pulmonary tumors which can produce more consistent and larger conformal ablation zones, access more tumor sites in a less invasive fashion, while under real-time image guidance. Specifically, tumor in the lung surrounded by air filled lung parenchyma is thermally insulated and will require less energy for a given volume of ablation. Catheter-based ultrasound (CBUS) is a novel thermal therapy technology with potential for dynamic and conformal spatial control of ablation, has effective energy penetration, and is delivered under CT-fluoro image guidance for real-time treatment targeting and delivery. In this proposal we plan to develop and establish the feasibility of catheter-based ultrasound technologies specific for lung tumor ablation using CT-fluoro guidance. Building upon the expertise of our group, we pose that catheter-based ultrasound devices can be developed to provide a technique for endobronchial or intraluminal treatment of lung tumors adjacent to central and peripheral airways, respectively, as well as small interstitial devices for a percutaneous approach. Favorable energy penetration across the bronchial wall and preferential absorption and reflection of ultrasound energy at the tumor margin preferentially localizes therapy within tumor and nearby surrounding margin, with larger volume heating possible. The objectives of this project are to (1) perform proof-of-concept development and determine feasibility of high-intensity endobronchial and percutaneous ultrasound for image guided thermal treatment of lung tumors and also minimize percutaneous device size while retaining volume ablation, (2) perform 3D anatomical biothermal simulation studies toward applicator design and development of therapy delivery strategies, (3) implement new devices and demonstrate targeting within lung tumor alone for guidance of catheter-based ultrasonic ablation, and perform in situ evaluations of the endobronchial and percutaneous ultrasound catheters under MDCT image guidance in a porcine model, applying delivery strategies and techniques as developed herein. We anticipate that given a positive outcome of this exploratory study, the devices and imaging techniques can be further developed and evaluated more extensively in animal trials and eventual human pilot studies. Significant potential advantages of this technology include less invasive endobronchial and intraluminal access to more tumor sites, precision ablation of larger volumes, real-time control and treatment verification, thus improving response, reducing complications, and benefiting a greater number of patients.